LANOTAN

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT LANOTAN® (LANOTAN)

Composition:

Active substance: latanoprost;

1 ml of the preparation contains 0.05 mg of latanoprost;

Excipients: benzalkonium chloride, sodium dihydrogen phosphate monohydrate, sodium hydrogen phosphate anhydrous, sodium chloride, water for injections.

Pharmaceutical form. Eye drops.

Main physicochemical properties: clear, colorless liquid.

Pharmacotherapeutic group. Antiglaucoma agents and miotics. Prostaglandin analogues. ATC code S01E E01.

Pharmacological properties.

Pharmacodynamics.

The active substance latanoprost, a prostaglandin F2α analog, is a selective agonist of the prostaglandin FP receptor, reducing intraocular pressure by increasing the outflow of aqueous humor. Reduction of intraocular pressure in humans begins approximately 3–4 hours after administration of the drug, with maximum effect observed within 8–12 hours. The hypotensive effect lasts for at least 24 hours.

Preclinical studies have shown that latanoprost is effective as monotherapy. In addition, clinical studies on combination therapy have been conducted. These included studies demonstrating that latanoprost is effective in combination with beta-adrenergic blockers (timolol). Short-term (1 or 2 weeks) studies indicate that the effect of latanoprost is additive when used in combination with adrenergic agonists (dipivefrin), oral carbonic anhydrase inhibitors (acetazolamide), and at least partially additive when used with cholinergic agonists (pilocarpine).

Clinical studies have shown that latanoprost does not significantly affect the production of intraocular fluid. No effect of latanoprost on the blood-ocular barrier has been observed.

Latanoprost did not cause leakage of fluorescein into the posterior segment of pseudophakic human eyes during short-term treatment.

No significant pharmacological effect of latanoprost on the cardiovascular and respiratory systems has been observed at clinical doses.

Pharmacokinetics.

Latanoprost (molecular weight 432.58) is an isopropyl ester of the active substance, i.e., a prodrug that is inactive per se but becomes biologically active after hydrolysis to form latanoprost acid.

Prodrugs penetrate well through the cornea, and all of the drug reaching the intraocular fluid is hydrolyzed during passage through the cornea.

Studies in humans have shown that maximum concentration in the intraocular fluid is achieved approximately 2 hours after topical administration. After topical administration in monkeys, latanoprost is distributed primarily in the anterior segment, conjunctiva, and eyelids. Only a negligible amount of the drug reaches the posterior segment.

There is virtually no metabolism of latanoprost acid within the eye. The main metabolism of the drug occurs in the liver. In humans, the plasma half-life is 17 minutes.

Clinical characteristics.

Indications.

To reduce elevated intraocular pressure in patients with open-angle glaucoma and ocular hypertension.

To reduce elevated intraocular pressure in pediatric patients with ocular hypertension and childhood glaucoma.

Contraindications.

Known hypersensitivity to any component of the medicinal product.

Interaction with other medicinal products and other forms of interaction.

Comprehensive data on interactions with other medicinal products are lacking.

Paradoxical increase in intraocular pressure has been reported after concomitant ocular administration of two prostaglandin analogues. Therefore, concomitant use of two or more prostaglandins, prostaglandin analogues, or their derivatives is not recommended.

Drug interaction studies have been conducted only in adult patients.

Special precautions for use.

Lanotan® may cause a gradual change in eye color due to increased brown pigment in the iris. Patients should be informed about the possibility of permanent eye color change before initiating treatment. Treatment of only one eye may lead to permanent heterochromia.

Changes in eye color are predominantly observed in patients with mixed iris pigmentation, such as blue-brown, gray-brown, yellow-brown, or green-brown. In clinical studies with latanoprost, color changes typically occurred within the first 8 months of treatment, less frequently during the second or third year, and were not observed after the fourth year of treatment. Progression of iris pigmentation decreases over time and stabilizes after 5 years. The effect of enhanced pigmentation after 5 years of treatment has not been evaluated. In an open-label 5-year safety study of latanoprost, increased iris pigmentation was recorded in 33% of patients (see section "Adverse reactions"). Iris color changes are mostly mild and often clinically unnoticeable. The incidence of cases in patients with mixed iris color ranged from 7% to 85%, with the highest frequency observed in patients with yellow-brown iris color. Eye color changes were not observed in patients with uniformly blue eyes and were rare in patients with uniformly gray, green, or brown eyes.

The color change occurs due to increased melanin content in the iris stromal melanocytes, not due to an increase in the number of melanocytes. Typically, brown pigmentation spreads concentrically from around the pupil toward the periphery of the affected eye, although the entire iris or parts of it may become more brown. No further progression of brown iris pigmentation has been observed after discontinuation of treatment. Currently, clinical studies have not provided evidence linking this phenomenon to any symptoms or pathological changes.

No changes in iris nevi or freckles have been observed under the influence of therapy. Clinical studies have not shown pigment accumulation in the trabecular meshwork or any other part of the anterior chamber of the eye. Results from drug use indicate that increased iris pigmentation does not lead to clinical complications, and latanoprost treatment may be continued if iris pigmentation changes occur. However, patients should undergo regular examinations, and if the clinical situation requires, treatment with Lanotan® should be discontinued.

Experience with the use of Lanotan® is limited in chronic angle-closure glaucoma, open-angle glaucoma in pseudophakic patients, and pigmentary glaucoma. Currently, there are no data on the use of Lanotan® in inflammatory or neovascular glaucoma, or in inflammatory eye diseases. Lanotan® has no or minimal effect on the pupil, but data on its use during acute attacks of angle-closure glaucoma are lacking. Therefore, Lanotan® should be used with caution in such conditions until more data become available.

Data on the use of Lanotan® during the perioperative period of cataract surgery are limited. These patients should be treated with Lanotan® with caution.

Lanotan® should be used with caution in patients with a history of herpetic keratitis, but its use should be avoided in cases of active herpetic keratitis caused by herpes simplex virus and in patients with a history of recurrent herpetic keratitis, especially if associated with prostaglandin analogs.

Cases of macular edema have been reported (see section "Adverse reactions"), primarily in aphakic patients, pseudophakic patients with posterior capsule rupture or anterior chamber lenses, and patients with known risk factors for cystoid macular edema (such as diabetic retinopathy and retinal vein occlusion). Lanotan® should be used with caution in aphakic patients, pseudophakic patients with posterior capsule rupture or anterior chamber lenses, and patients with known risk factors for cystoid macular edema.

Lanotan® may be used with caution in patients with known risk factors for development of iritis/uveitis.

Experience with the use of the drug in patients with bronchial asthma is limited, although some cases of asthma exacerbation and/or dyspnea have been reported during the post-marketing period. Until sufficient clinical experience is accumulated, the drug should be prescribed with caution to patients with bronchial asthma (see also section "Adverse reactions").

Changes in skin color in the periorbital area have been observed, with most cases reported in Japanese patients. Available data suggest that skin pigmentation changes in the periorbital area are not permanent and may resolve during continued treatment with Lanotan®.

Latanoprost may gradually alter the eyelashes and vellus hair around the treated eye and adjacent areas, including increased length, thickness, pigmentation, and number of eyelashes or vellus hairs, as well as misdirected eyelash growth. These eyelash changes are reversible and resolve after discontinuation of the drug.

Lanotan® contains benzalkonium chloride, commonly used as a preservative in ophthalmic preparations. Reports indicate that benzalkonium chloride may cause punctate keratopathy and/or toxic ulcerative keratopathy. It may also cause eye irritation and discoloration of soft contact lenses. Careful monitoring is required in patients with dry eye or corneal disorders when using Lanotan® frequently or long-term. Contact lenses may absorb benzalkonium chloride; therefore, they should be removed before administering Lanotan® and may be reinserted 15 minutes after instillation (see section "Dosage and administration").

Use during pregnancy or breastfeeding.

Pregnancy

The safety of this medicinal product for use in pregnant women has not been established. Its pharmacological action poses a potential risk to pregnancy, the fetus, or the newborn. Therefore, Lanotan® should not be used during pregnancy.

Breastfeeding

Latanoprost and its metabolites may pass into breast milk; therefore, mothers who are breastfeeding should either discontinue treatment with Lanotan® or stop breastfeeding.

Ability to affect reaction speed when driving or operating machinery.

As with other ophthalmic drops, instillation may cause transient blurred vision. Patients should refrain from driving vehicles or operating machinery until this effect subsides.

Method of Administration and Dosage

Recommended dosage for adults, including elderly patients

Recommended therapy: 1 drop in the affected eye once daily. The optimal effect is achieved when Lanotan® is administered in the evening.

Lanotan® should not be used more frequently than once daily, as more frequent administration has been shown to reduce the intraocular pressure-lowering effect.

If a dose is missed, treatment should be continued with the next dose at the usual time.

As with any ophthalmic drops, to minimize potential systemic absorption after instillation, it is recommended to press the lacrimal sac at the medial canthus of the eye (punctal occlusion) for 1 minute. This should be done immediately after instilling each drop.

Contact lenses should be removed before instilling ophthalmic drops and may be reinserted 15 minutes after administration.

When using multiple locally acting ophthalmic agents, the products should be administered with an interval of at least 5 minutes.

Children

Lanotan® ophthalmic drops may be used in pediatric patients at the same dosage as in adults.

Data on efficacy and safety of the drug in patients under 1 year of age are very limited. There are no available data on use in preterm infants (born before 36 weeks of gestation).

In children from birth to 3 years of age, primarily suffering from primary congenital glaucoma, surgical intervention (e.g., trabeculotomy/goniotomy) remains the first-line treatment.

Long-term safety of the drug in pediatric patients has not been established.

Overdose

Apart from eye irritation and conjunctival hyperemia, no other ocular adverse effects have been reported in cases of overdose with Lanotan®.

The following information may be helpful in case of accidental ingestion of Lanotan®. One bottle contains 125 mcg of latanoprost. More than 90% is metabolized during first-pass liver metabolism. Intravenous infusion of latanoprost at a dose of 3 mcg/kg in healthy volunteers did not cause any symptoms; however, doses of 5.5–10 mcg/kg caused nausea, abdominal pain, dizziness, increased fatigue, flushing, and sweating.

However, when latanoprost was administered locally into the eyes at doses 7 times higher than the clinical dose of Lanotan®, no bronchoconstriction was observed in patients with mild to moderate bronchial asthma.

In case of overdose with Lanotan®, symptomatic treatment should be administered.

Adverse reactions.

Most adverse events are related to the eye. In an open-label 5-year study of latanoprost, iris pigmentation changes were recorded in 33% of patients (see section "Special precautions"). Other ophthalmological adverse events are usually temporary and occur after administration of the drug.

Infectious and parasitic diseases: Herpetic keratitis.

Nervous system disorders: Headache, dizziness.

Eye disorders: Increased pigmentation of the iris; mild to moderate conjunctival hyperemia; eye irritation (burning sensation, foreign body sensation, itching, stinging, sensation of sand in the eyes); changes in eyelashes and vellus hair (increased length, thickness, pigmentation, and number) (the majority of cases were observed in Japanese patients); transient punctate epithelial erosions, mostly asymptomatic; blepharitis; eye pain; photophobia; eyelid edema; dry eye; keratitis; blurred vision; conjunctivitis; iritis/uveitis (most cases occurred in patients with concomitant risk factors for these conditions); macular edema; symptomatic corneal edema and erosion; periorbital edema; misdirected eyelash growth, sometimes leading to eye irritation; development of an extra row of eyelashes near the meibomian gland orifices (distichiasis); periorbital changes and eyelid alterations leading to deepening of the eyelid fold; iris cyst.

Cardiac disorders: Unstable angina, tachycardia.

Respiratory, thoracic and mediastinal disorders: Bronchial asthma, exacerbation of bronchial asthma, dyspnea.

Gastrointestinal disorders: Uncommon – nausea, vomiting.

Skin and subcutaneous tissue disorders: Rash; local skin reaction on the eyelids; darkening of the palpebral skin of the eyelids.

Musculoskeletal and connective tissue disorders: Myalgia, arthralgia.

General disorders and administration site conditions: Chest pain.

Very rare cases of corneal calcification associated with the use of ophthalmic solutions containing phosphate have been reported in some patients with significantly damaged corneas.

Children

The safety profile of latanoprost in pediatric patients is similar to that in adults, and no new adverse events have been identified. Short-term safety profiles in different pediatric subgroups were also similar. In pediatric patients, the following adverse events occur more frequently than in adults: nasopharyngitis and increased body temperature.

Shelf life. 2 years.

The shelf life of the medicinal product after opening the bottle is 42 days.

Do not use the medicinal product after the expiry date stated on the packaging.

Storage conditions.

Store in the original packaging at a temperature of 2 °C to 8 °C.

Keep out of the reach of children.

Packaging. 2.5 ml in a bottle, 1 unit.

Prescription status. Prescription only.

Manufacturer. JSC "Farmak".

Manufacturer's name and address of place of business.

74, Kyrylivska Street, Kyiv, 04080, Ukraine.